Human polymorphonuclear neutrophiclic leukocytes (PMNs) contain large amounts of neutral proteases that degrade elastine, collagen, proteoglycan, and abasement membrane. The instillation of one of the purified enzymes(elastase) into dog lungs in vivo causes degradation of elastic fibers and other alveolar septal components and results in anatomic changes similar to those of human pulmonary emphysema. Cigarette smoking is a major risk factor associated with pulmonary emphysema in man. One mechanism for this association may be interference, by smoke, with the regulation of PMN elastase activity by alveolar antiproteases. This possibility is supported by the observation that oxidizing activity of tobacco smoke inactivates alpha-l-proteinase inhibitor activity. A second major lung antiproteinase, the low molecular weight acid-stable bronchial mucous inhibitor, is also oxidatively inactivated by cigarette smoke in vitro and its activity is partly suppressed in tracheal aspirates obtained from chronic human smokers We plan next to examine the possible association between extent of lung proteinase inhibitor inactivation in chronic human smokers and extent of airflow obstruction in these individuals. We will also determine the redox state of lung inhibitors in these subjects and will search for possible protective effects of anti-oxidants in animal models of this system. Hopefully a unified hypothesis of lung injury in pulmonary emphysema can be constructed involving both PMN and macrophage elastases and the actions of cigarette smoke.